EP1842569A2 - Implants comprising FK506 - Google Patents

Abstract

Implant (A) contains FK506 in chemically bound (covalent or non-covalent) or physically fixed form and optionally at least one other active agent (II). Independent claims are also included for the following: (a) preparation of (A) optionally coated with active agents, and (b) a stent with a polymeric surface including, in chemically bound (covalent or non-covalent) or physically fixed form, at least one physiologically and/or pharmaceutically active agent. ACTIVITY : Vasotropic. MECHANISM OF ACTION : None given in the source material.

Description

The invention relates to implants, in particular intracavernous or intravascular, preferably for the treatment or prophylaxis of coronary or peripheral vascular occlusions or vascular constrictions, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis, in chemically covalently or non-covalently bound or physically fixed Form FK506, process for their preparation and their use.

The formation of atherosclerotic lesions in the arterial blood vessels is the underlying disease for a wide range of clinical symptoms, ranging from angina pectoris to intermittent claudication to myocardial infarction and ischemic stroke; all based on atheroma formation and / or stenotic lesions. The term stenotic lesions refers to the local reduction of the vessel lumen to less than 60-70% of its normal diameter, which in turn leads to a significant reduction in the supply of oxygen and nutrients to the respective tissue. Although pharmacotherapy (statins, ACE inhibitors, gplla / IIIb blockers and plasminogen activators) has achieved good therapeutic success in recent decades, especially in the area of cardiovascular diseases, surgical intervention (bypass surgery, etc.) is still required in many patients who have developed a complete ischemic condition. Moreover, these operations are relatively complicated and costly and involve the risk of serious complications.

To prevent the development of ischemic heart disease, minimally invasive surgical procedures have been developed. The invention of percutaneous transluminal coronary angioplasty (Percutaneous Transluminal Coronary Angioplasty / PTCA) in the late 1970's was a big breakthrough in cardiology. The PTCA uses inflatable balloons that are advanced into the coronary arteries until stenotic lesion. These balloons are then inflated at the respective target positions and achieve a dilatation of the stenotic region. A similar procedure can also be used in the dilation of the carotid or peripheral arteries.

Nevertheless, it was soon discovered that a relatively large proportion of PTCA patients developed reoccurring stenosis at sites that had been dilated with the balloon catheter. It was discovered that this so-called restenosis is caused by a new formation of the vascular architecture of the tissue layers. The introduction of tubular vascular metal implants, so-called stents, in the transluminal treatment of the stenosis improved the situation. In clinical trials ( Serruys et al., N. Engl. J. Med. 331 (1994) 489-495 ), it has been demonstrated that the use of stents at the balloon-dilated sites could reduce the incidence of restenosis from about 45% to about 30%. Although this is already considered to be a significant improvement in the prevention of residual restenosis, there is still a significant incentive for therapeutic improvements.

Detailed studies of the pathophysiology of restenosis in the stent have revealed that it differs from PTCA-induced restenosis. Inflammatory responses, hyperproliferation, and smooth muscle cell (SMCs) migration are important factors in neointimal formation leading to restenosis in the stent. It has been found in the animal-restenosis model, and even in human tissue, that the hyperproliferation of the SMCs with infiltration of the tissues around the stiffener stent by macrophages and T cells ( Grewe et al., J. Am. Coli. Cardiol. 35 (2000) 157-63 ). By analogy with other clinical indications in which Inflammatory reactions and hyperproliferation of cells play a role and can be controlled by drug treatment has also been attempted to treat restenosis by pharmacotherapy. Selected drugs were given either orally or intravenously, or delivered to the site of action through perforated catheters. Unfortunately, to date, none of these agents has been able to significantly reduce restenosis ( Gruberg et al., Exp. Opin. Invest. Drugs 9 (2000) 2555-2578 ).

The direct delivery of pharmacologically active agents from drug-coated stents is the method of choice here. Animal studies and preliminary results of clinical trials with drug-coated stents appear to indicate that sustained release of immunosuppressive or antiproliferative drugs may reduce the risk of restenosis. Paclitaxel, a cytostatic drug and rapamycin, an immunosuppressive and cytostatic agent, have been tested in animal studies. Both compounds inhibit neointima formation ( Herdeg et al., Semin Intervent Cardiol 3 (1998) 197-199 ; Hunter et al., Adv. Drug. Delivery Rev. 26 (1997) 199-207 ; Burke et al., J Cardiovasc Pharmacol., 33 (1999) 829-835 ; Gallo et al., Circulation 99 (1999) 2164-2170 ). Nevertheless, after 6 months of implantation of coated stents in pigs with paclitaxel, a reversal of the effect was observed ( Heldman, International Local Drug Delivery Meeting and Cardiovascular Course on Radiation, Geneva, Jan. 25-27, 2001 ). Rapamycin showed good efficacy with complete abolition of restenosis in initial clinical applications ( Sousa et al., Circulation 103 (2001) 192-195 ). On the other hand, this seems to go hand in hand with slower healing of the vessel wall injured by balloon angioplasty and stent placement.

Generally speaking, there is a balance between healing of the arterial vessel wall after angioplasty and stent placement on the one side and curbing neointima formation of great importance. To achieve this balance, agents should be used that selectively interfere with specific mechanisms leading to neointima formation.

It was therefore an object of the invention to provide implants with favorable properties for the treatment and prophylaxis of restenosis.

The invention therefore relates to an implant containing in chemically covalently or non-covalently bonded or physically fixed form FK506 and optionally at least one further active ingredient.

For each active ingredient mentioned in the context of this invention, including the active ingredient FK506, the term active substance also describes direct derivatives of the active ingredient and also the active ingredient in all types of salts, enantiomers, racemates, bases or free acids of the active ingredient and mixtures thereof.

It is preferred if the implant is an intracavernous, preferably an intravascular implant.

This is understood to mean intracavernous within a cavity, in particular within a hollow organ or hollow organs such as blood vessels, esophagus, ureter, bile ducts etc.

By intravascular is meant in particular the use in a blood vessel.

It is also preferred if the implant is suitable for the treatment or prophylaxis of coronary or peripheral vascular constrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis.

Therefore, an intracavernous, preferably intravascular implant is particularly preferred for the treatment or prophylaxis of coronary or peripheral vascular constrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prevention of restenosis, contained in chemically covalently or non-covalently bound or physically fixed Form FK506 and optionally at least one further active ingredient.

The macrolide antibiotic FK506 (tacrolimus, [3S- [3R * [E (1S *, 3S *, 4S *)], 4S *, 5R *, -8S *, 9E, 12R *, 14R *, 15S *, 16R * , 18S *, 19S *, 26aR *]] - 5, 6, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 25, 26, 26a-hexadecahydro-5, 19-dihydroxy-3- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methylenthenyl] -14.16-dimethoxy-4,10,12,18-tetramethyl-8- (2-propenyl) -15, 19-epoxy-3H-pyrido [2,1-c] [1,4] oxaazacyclotricosine-1,7, -20,21 (4H, 23H) -tetrone; Merck index no. 9000.) is one developed for transplantation medicine active ingredient. FK506 inhibits the release of interleukin-2 (IL-2) and interferon-γ (IFN-γ) from T cells, thereby blocking implant (graft) rejection ( Wiederrecht et al., Ann. NY Acad Sci. 696 (1993) 9-19 ). FK506 has also been used in SMC cultures for inhibition of smooth muscle cell proliferation ( Mohacsi et al., J. Heart Lung Transplant. 16 (1997) 484-492 ; Marx et al., Circulation Res., 76 (1995) 412-417 ) and their migration ( Poon et al., J. Clin. Invest. 98 (1996) 2777-2283 ). In general, FK506 was considered unsuitable by several researchers for its low potency for the prevention of restenosis (Mohacsi et al, (1997); Poon et al. (1996); Marx et al., 1995; Dell, Curr Med Chem 5 (1998) 179-94 ). Mohacsi et al. found a half-maximal inhibition of SMC proliferation between 100 nM and 1 μM, whereas Marx et al. observed no effect at concentrations up to 123 nM. In contrast, rapamycin is active in inhibiting the proliferation of SMC cultures in the nanomolar concentration range.

On the basis of this prior art, the use of just FK506 for the inhibition of restenosis did not appear to be promising at all (Mohacsi et al. (1997); Poon et al. (1996)). Surprisingly, contrary to the opinion of the experts, it has been shown that the use of FK506 in particular as part of a stent but also of other implants is very effective in the treatment and prophylaxis of restenosis. Especially the local administration of FK506 is favorable for the prevention of restenosis and the effect is very balanced, because it also allows a good re-endothelialization of the injured vessel wall.

Without assuming this in the first place, this could possibly be explained by the immunomodulatory activity of FK506, which results in a half-maximal inhibition of IL-2 release at concentrations around 0.1 nM (FIG. Kino et al., J. Antibiot. 40 (1987) 1256-1265 ) and an inhibitory effect on SMC proliferation at concentrations around 300-500 nM. Accordingly, the use of FK506 is correspondingly favorable.

Stenosis is the occlusion or narrowing of a vessel and restenosis is the recurrence of a stenosis.

Further, by "including" is meant, inter alia, also an example not covalently bound coating.

Further, "peripheral" refers in particular to vessels or other hollow organs outside the heart and the coronary arteries.

By "chemically non-covalently bound" are meant in particular bonds through interactions such as hydrogen bonds, hydrophobic interactions, Van der Waals forces, etc.

By physically fixed, for example, trapping is e.g. to understand by a membrane in a hole or steric Entrapment by choice of the opening sizes etc ..

An implant is any form of an artificial object that is inserted (even for a limited time). In particular, these are intracavernous, for example, intravascular implants. Examples include stents, grafts, stent grafts, graft connectors, guidewires, catheter pumps or catheters.

For the purposes of this invention, a stent is understood to be an elongated, hollow internally implant having at least two openings and usually a circular or elliptical but also any other cross section (usually made of metal but possibly also of plastic materials or polymers) of preferably openwork, lattice-like structure in vessels, especially blood vessels is implanted to keep them open or functional.

For the purposes of this invention, graft is understood to mean an elongate, hollow internally implant having at least two openings and usually a circular or elliptical but also any other cross section and having at least one homogeneous or optionally of different strands, closed and for corpuscular blood components and / or for Water-impermeable polymer surface, which generally serves as a vascular prosthesis and is usually used in damaged vessels or instead of vessels.

For the purposes of this invention, stent graft is the connection between stent and graft. Correspondingly, a stent graft is basically a stent-reinforced vascular prosthesis (graft, supra), the polymer layer being woven, closed and closed for corpuscular blood components and / or water, homogeneously or optionally from different strands. In the narrower sense, this is a stent which on at least 20% of the surface of the implant has a perforated (lattice-shaped), preferably metallic outer layer and at least one homogeneous or possibly woven from different strands, closed and for corpuscular blood components lying inside or outside of this outer layer. or water-impermeable polymer layer and optionally (in the case of external perforated layer) another, inside of the polymer layer, openwork (lattice) preferably metal inner layer or a lying outside and outside of the open layer homogeneous or optionally woven from different strands, closed and for corpuscular blood components and / or water-impermeable polymer layer.

For the purposes of this invention, a graft connector is an implant which connects at least two hollow organs, vessels or grafts, consists of the materials defined for grafts or stent grafts and / or has the structure defined for them and accordingly has at least two, preferably three or four openings, in particular an asymmetrical "T" shape shows.

For the purposes of this invention, a catheter is understood to mean a tubular instrument for insertion into hollow organs. In the narrower, preferred sense, they are guide, angiographic or balloon catheters.

For the purposes of this invention, a catheter pump is understood to mean a catheter provided with a propeller at its tip, which can assist the pumping of the heart muscle.

It is a further preferred embodiment of the implant according to the invention if the implant has at least one of a metal or a metal alloy, homogeneous or formed of different strands, closed or perforated layer or surface.

Under metal or metal alloy in the context of this invention, in particular steel or steel alloys but also nickel or nickel alloys are to be understood, the term metal already encompassed from the outset also metal alloys.

Broken-open are in particular lattice-shaped, woven or braided structures.

It is a further preferred embodiment of the implant according to the invention if the implant has at least one closed or perforated layer or surface made of a polymer, homogeneous or formed of different strands.

In a preferred embodiment, the implant has at least one polymer layer which is wholly or partially composed of a metal or a metal alloy, homogeneous or formed from different strands, closed or open-ended layer or surface, preferably one consisting of a metal or a metal alloy, optionally latticed structure, covered.

In a particularly preferred embodiment, the implant comprises at least one of a metal or a metal alloy, homogeneous or formed from different strands, closed or perforated layer or surface and at least one consisting of a polymer, homogeneous or formed from different strands, closed or openwork layer or surface on.

In this case, it is particularly preferred if, in the case of this implant, the layer or surface consisting of a metal or a metal alloy is an optionally lattice-shaped structure consisting of a metal or a metal alloy and / or the layer or surface consisting of a polymer is homogeneously closed or woven and / or is water and / or Korpuskelundurchlässig and / or the sequence of the layers and surfaces from outside to inside metal polymer, polymer metal, metal polymer metal or polymer metal polymer and / or either of a Polymeric layer or surface is not chemically (covalently or noncovalently bonded) to the metal or metal alloy layer or surface or polymer layer or surface by means of an adhesive with the metal or metal alloy layer or surface connected is.

It is further preferred if the polymer used in the context of the implants is selected from Dacron; Polytetrafluoroethylene (PTFE / Teflon), expandable or non-expandable; or polyurethane; preferably made of polytetrafluoroethylene (PTFE), expandable or non-expandable; or polyurethane; in particular made of PTFE.

It is also a preferred embodiment of the invention if the implant is a stent, a stent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, a stent graft, a graft or a graft Connector, in particular a stent or a stent graft.

It is particularly preferred if the implant according to the invention is coated with FK506.

Local application of FK506 is achieved by direct delivery from the drug-loaded surface of a coronary or peripheral stent. A drug-loaded surface of a stent can be achieved by using various technological approaches. Each of these approaches can be carried out so that the active ingredient is released from the surface either in a short (hours) or an extended period (days). The release kinetics can be adjusted by making specific modifications to the surface, e.g. hydrophobic or hydrophilic side chains of a polymeric carrier or a ceramic surface. These surfaces, too, can in turn be modified on the surface, eg. by Si groups on an alumina layer.

The release kinetics can be adapted by using specific polymers, block polymers, polymer blends, graft polymers alone or in layered form. Particularly suitable for controlling the release kinetics is the use of nanocapsules and / or Liposomes and the polymer combinations described above. Nanocapsules are generally understood to be the encapsulation of micellar systems or colloidal solids into ultrafine particles with a solid coating. The coated particles, whose size is in the nanometer range, dissolve colloidally. Nanocapsulated agents can be used with prolonged efficacy. Liposomes are generally formed from phospholipids by dispersing in aqueous media and are of interest in this context because hydrophilic drugs can be incorporated into the aqueous interior volume as well as the aqueous interlayers and hydrophobic drugs in the lipid layers. If nanocapsules and / or liposomes are used in different compositions, they can be loaded with various active substances, thus selectively releasing a combination of active substances.

Ceramic coating

An alumina coating (patent applications DE 19855421 . DE 19910188 . WO 00/25841 ) with a porous surface can be loaded with FK506 in amounts between 10 μg and 10 mg either by immersion, spraying or a comparable technique. The dose of the drug depends on the nature of the target vessel and the condition of the patient and is chosen so as to sufficiently inhibit proliferation, migration and T cell response without hindering the healing process. FK506 can be used as an aqueous or organic solution, for example in DMSO, DMF and ethanol. After spraying or dipping (optionally under a slight vacuum), the treated stent is dried and the procedure is repeated 2-10 times. Another possibility in the application is the direct application of the drug solution to the stent strands with the aid of a micropipette or a pipetting robot. After the last drying step, the stent may be left in water or at room temperature for one minute Isotonic saline rinsed and then dried again. The active ingredient content can be analyzed by dissolving the active ingredient with a suitable solvent by standard methods (HPLC, LC-MS). Release kinetics can be measured using a standard release measuring apparatus. The ceramic batch can be combined with a polymeric (optionally biodegradable) coating.

Incidentally, any type of metal oxide coatings can be used analogously, in particular, for example, iridium oxide as in the patent US6,245,104 B1 described. Accordingly, any mention of alumina is to be understood hereinafter as including other metal oxides such as iridium oxide.

PTFE membrane: stent graft

Here, a similar approach to that described above is used. FK506 is stored in the wells of the porous PTFE membrane.

General polymeric coating

Various polymers are suitable for drug loading: methacrylate polymers, polyurethane coatings, PTFE coatings, hydrogel coatings, The active ingredient can either be applied to the final surface (see above) or added directly to the polymerization solution. In the remaining details this technical approach corresponds to that already described above.

Various polymers as well as combinations of these in the form of polymer blends, layered systems, block copolymers, graft polymers can be used. Suitable polymers are: Acrylates and methacrylates, silicones such as polydimethylsiloxane, polymethylenemalon esters, polyethers, polyesters, bioresorbable polymers, polymers of vinylic monomers such as polyvinylpyrrolidone and vinyl ethers, poly-cis-1,4-butadiene, poly-cis-1,4-isoprene, poly Trans-1,4-isoprene and vulcanized products, polyurethanes, polyureas, polyamides, polyimides, polysulfones and biopolymers such as cellulose and its derivatives and proteins and fibrin glue. Particularly interesting properties show hydrogels which have very good hemocompatibility because of their high water absorption as the outermost layer (top coat). Here, hydrogels such as polyacrylamide, polyacrylic acid, polymers with oxygen as a heteroatom in the main chain such as polyethylene oxide, polypropylene oxide, polytetrahydrofuran can be used. The active ingredient can either be applied to the final surface or embedded in nanocapsules and / or liposomes. However, the active ingredient may also be contained directly in the polymerization solution or in the polymer solution. In some polymer / drug systems, the drug can be immobilized by swelling.

Mechanical approach

The mechanical approach is based on depressions that are introduced into the stent struts by means of a laser. These wells can then be filled with FK506. The mechanical (wells) approach can be combined with a polymeric, optionally biodegradable coating that itself is drug loaded. After an initial release from the polymeric coating drug can be released from the drug-filled wells in the long term. In the remaining details this technical approach corresponds to that already described above.

Accordingly, it is a further preferred embodiment of the implant according to the invention, when the implant has a ceramic coating, in particular of aluminum oxide, is bound to the FK506.

It is a further preferred embodiment of the implant according to the invention if the implant has a polymeric coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel / polyurethane blend, in particular PTFE, bound to the FK506 or in the FK506 before application of the coating has been solved.

It is a further preferred embodiment of the implant according to the invention if the metal of the implant has laser-introduced wells filled with FK506. It is particularly advantageous if the metal provided with FK506-filled depressions or at least the wells is / are coated with a biodegradable polymer material, optionally FK506 is bound to the polymeric coating or FK506 was dissolved in the polymer material before the polymerization of the coating ,

1. a) ein wenigstens eine aus einem Metall oder einer Metall-Legierung bestehende, homogene oder aus verschiedenen Strängen gebildete, geschlossene oder durchbrochene Schicht oder Oberfläche aufweisendes Implantat gemäß einem der Ansprüche 4, 6 oder 7 bis 10, das mit einem keramischen Überzug, insbesondere aus Aluminiumoxid, überzogen wird, eingesetzt wird
   oder
2. b) ein wenigstens eine aus einem Polymer bestehende, homogene oder aus verschiedenen Strängen gebildete, geschlossene oder durchbrochene Schicht oder Oberfläche aufweisendes Implantat gemäß einem der Ansprüche 5 bis 10 eingesetzt wird,
   oder
3. c) ein Implantat gemäß einem der Ansprüche 1 bis 10, das mit einem polymerisierten oder auf der Oberfläche polymerisierenden Überzug, insbesondere aus Methacrylat-Polymeren, Polyurethan, PTFE, Hydrogel oder Hydrogel/Polyurethan-Blend, überzogen wird, eingesetzt wird
   oder
4. d) ein Implantat gemäß einem der Ansprüche 4, 6 oder 7 bis 10 mit wenigstens einer aus einem Metall oder einer Metall-Legierung bestehenden, homogenen oder aus verschiedenen Strängen gebildeten, geschlossenen oder durchbrochenen Schicht oder Oberfläche, in die mittels eines Lasers Vertiefungen eingebracht werden, die mit FK506 gefüllt werden, und dann das Implantat mit einem polymerisierten oder auf der Oberfläche polymerisierenden bioabbaubaren Überzug überzogen wird, eingesetzt wird,
5. e) dann das Implantat gemäß a), b), c) oder d) mit einer FK506-Lösung in wäßrigem oder organischem Lösungsmittel in Kontakt gebracht wird, beispielsweise durch Beträufeln, Besprühen oder Eintauchen gegebenenfalls unter Vakuum,
6. f) dann gegebenenfalls das Implantat getrocknet wird, vorzugsweise bis zur Entfernung des Lösungsmittels aus Schritt e),
7. g) dann gegebenenfalls Schritt e) gegebenenfalls gefolgt von Schritt f) wiederholt wird, vorzugsweise mehrfach, insbesondere 1 bis 5-fach, sowie
8. h) gegebenenfalls anschließend das Implantat ein- oder mehrfach mit Wasser oder isotoner Saline gespült wird und
9. i) gegebenenfalls anschließend getrocknet wird.

In another very favorable embodiment of the implant according to the invention, the implant can be produced by a method in which

1. a) at least one consisting of a metal or a metal alloy, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 4, 6 or 7 to 10, with a ceramic coating, in particular Alumina is coated, is used
   or
2. b) at least one of a polymer, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 5 to 10 is used,
   or
3. c) an implant according to any one of claims 1 to 10, which is coated with a polymerized or surface-polymerizing coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel / polyurethane blend, is used
   or
4. d) an implant according to any one of claims 4, 6 or 7 to 10 with at least one consisting of a metal or a metal alloy, homogeneous or formed from different strands, closed or perforated layer or surface into which recesses are introduced by means of a laser which are filled with FK506 and then the implant is coated with a polymerized or surface-polymerizing biodegradable coating,
5. e) then the implant according to a), b), c) or d) is brought into contact with a FK506 solution in an aqueous or organic solvent, for example by dribbling, spraying or dipping optionally under vacuum,
6. f) then optionally the implant is dried, preferably until the removal of the solvent from step e),
7. g) then, if appropriate, step e) is repeated, if appropriate followed by step f), preferably several times, in particular from 1 to 5 times, and also
8. h) optionally then the implant is rinsed one or more times with water or isotonic saline, and
9. i) optionally subsequently dried.

It is preferred if in the production of this implantable implant according to the invention in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 0.5-5 g / l in FK506 in ethanol and / or in step e ) the implant is brought under vacuum, preferably by overnight immersion with a FK506 solution in aqueous or organic solvent in contact and / or steps f) and / or g) are not performed and / or in step h) the implant several times Saline is washed and / or in step i) the implant is dried overnight.

In an alternative particularly preferred embodiment of the invention, it is preferred if in the production of this implant according to the invention can be prepared in step e), the implant, preferably sterile, in a preferably sterile vessel with a perforable closure, for example after closing a perforation is introduced into an injection bottle, FK506 solution, preferably sterile, is filled into the vessel, which is closed with the perforation closure closing after the end of a perforation, a thin, preferably sterile, air-permeable ventilation tube, for example a cannula, vacuum is applied through the closure, a vacuum applied and preferably the FK506 solution is moved and finally, preferably after about 12 hours, the thin, preferably sterile, air-permeable vent tube is removed and / or in step e) FK506 in alcohol Geloë st, preferably in ethanol, in particular in a concentration of 3.3 mg FK506 in 1 ml of ethanol and / or that the implant remains until use in the preferably sterile closed glass vessel of step e) and / or steps f) to i) remain under.

In another very favorable embodiment of the implant according to the invention, the implant can be produced by a A method in which prior to formation of at least one polymeric, closed or open-ended layer or surface or polymeric coating of the FK506 implant was dissolved in the polymerization material.

1. a) innerhalb von < 48 h oder
2. b) über mindestens 48 h, vorzugsweise über mindestens 7 Tage, insbesondere über mindestens 2 bis zu 21 Tagen freigesetzt wird, oder daß
3. c) das Implantat beide Freisetzungsmuster a) und b) zeigt.

It is further particularly preferred if, after implantation of the implant according to the invention, FK506 is released. It is particularly advantageous if the release is delayed. It is a particularly preferred embodiment of the invention, when FK506 is released from the implant over a period of 24 h, preferably 48h, in particular more than 96h after implantation. In particular, it is also beneficial if the FK506 is removed from the implant after implantation

1. a) within <48 h or
2. b) over at least 48 h, preferably for at least 7 days, in particular for at least 2 to 21 days is released, or that
3. c) the implant shows both release patterns a) and b).

Especially the latter variant can be achieved by choosing two different types of coating, bonding or physical fixation. One example is FK506 laser wells sealed with FK506-loaded biodegradable membranes. After rapid release from the membrane is released in the long term from the wells.

• (Gruppe 1:) Molsidomin, Linsidomin, Natrium-Nitroprussid, Nitroglycerin oder allgemeinen NO-Donoren; Stimulatoren der löslichen Guanylat-Cyclase (sGC/soluble guanylate cyclase), beispielsweise BAY 41-2212 (5-(Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Hydralazin; Verapamil, Diltiazem, Nifedipin, Nimodipin oder anderen Ca²⁺-Kanal-Blockern; Captopril, Enalapril, Lisinopril, Quinapril oder anderen Inhibitoren Angiotensin umwandelnder Enzyme (angiotensin converting enzyme inhibitors); Losartan, Candesartan, Irbesartan, Valsartan oder anderen Antagonisten des Angiotensin II-Rezeptors;
• (Gruppe 2:) Dexamethason, Betamethason, Prednison oder anderen Corticosterioden; 17-beta-Östradiol; Cyclosporin; Mycophenol-Säure; VEGF, VEGF-Rezeptor Aktivatoren; Tranilast; Meloxicam, Celebrex, Vioxx oder anderen COX-2 Antagonisten; Indomethacin, Diclofenac, lbuprofen, Naproxen oder anderen COX-9-lnhibitoren; Inhibitoren des Plasminogen Aktivators-1 (plasminogen activator inhibitors-1) oder Serpinen; Thrombin Inhibitoren, beispielsweise Hirudin, Hirulog, Agratroban, PPACK oder Interleukin-10;
• (Gruppe 3:) Rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)-Rapamycin oder anderen Rapamycin-Derivativen; PDGF-Antagonisten; Paclitaxel oder 7-Hexanoyl-Taxol; Cisplatin; Vinblastin; Mitoxantron; Combretastatin A4; Topotecan; Methotrexat; Flavopiridol; Actinomycin D; Rheopro/Abciximab oder Probucol.

It is a further preferred embodiment of the invention if at least one further active substance is contained in the implant, preferably a pharmaceutical active substance, in particular a further active substance selected from the following active substances or their derivatives

• (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY 41-2212 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine] 3-yl] -pyrimidin-4-ylamines); hydralazine; verapamil, diltiazem, nifedipine, nimodipine or other Ca ²⁺ channel blockers; captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors (angiotensin converting enzyme inhibitors) Losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor;
• (Group 2 :) Dexamethasone, betamethasone, prednisone or other corticosteriodes; 17-beta-estradiol; cyclosporine; Mycophenolic acid; VEGF, VEGF receptor activators; tranilast; Meloxicam, Celebrex, Vioxx or other COX-2 antagonists; Indomethacin, diclofenac, lbuprofen, naproxen or other COX-9 inhibitors; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; Thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK or interleukin-10;
• (Group 3) rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl-taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; topotecan; Methotrexate; flavopiridol; actinomycin D; rheopro / abciximab or probucol.

It is particularly preferred that when the further active ingredient is selected from group 1, this is released from the implant within the first 24-72 h after implantation and / or, if the further active ingredient is selected from group 2, this from the implant within the first released 48 h - 21 days after implantation and / or, if the other active substance is selected from group 3, this is released from the implant within 14 days to 3 months after implantation.

Another object of the invention is a method for producing an implant according to the invention, in which prior to formation of at least one of a polymer, closed or perforated layer or surface or a polymeric coating of the implant FK506 was dissolved in the polymerization material.

1. a) ein wenigstens eine aus einem Metall oder einer Metall-Legierung bestehende, homogene oder aus verschiedenen Strängen gebildete, geschlossene oder durchbrochene Schicht oder Oberfläche aufweisendes Implantat gemäß einem der Ansprüche 4, 6 oder 7 bis 10, das mit einem keramischen Überzug, insbesondere aus Aluminiumoxid, überzogen wird,
   oder
2. b) ein wenigstens eine aus einem Polymer bestehende, homogene oder aus verschiedenen Strängen gebildete, geschlossene oder durchbrochene Schicht oder Oberfläche aufweisendes Implantat gemäß einem der Ansprüche 5 bis 10,
   oder
3. c) ein Implantat gemäß einem der Ansprüche 1 bis 10, das mit einem polymerisierten oder auf der Oberfläche polymerisierenden Überzug, insbesondere aus Methacrylat-Polymeren, Polyurethan, PTFE, Hydrogel oder Hydrogel/Polyurethan-Blend, überzogen wird,
   oder
4. d) ein Implantat gemäß einem der Ansprüche 4, 6 oder 7 bis 10 mit wenigstens einer aus einem Metall oder einer Metall-Legierung bestehenden, homogenen oder aus verschiedenen Strängen gebildeten, geschlossenen oder durchbrochenen Schicht oder Oberfläche, in die mittels eines Lasers Vertiefungen eingebracht werden, die mit FK506 gefüllt werden, und dann das Implantat mit einem polymerisierten oder auf der Oberfläche polymerisierenden vorzugsweise bioabbaubaren Überzug überzogen wird,
   wird eingesetzt,
5. e) dann wird das Implantat gemäß a), b), c) oder d) mit einer FK506-Lösung in wäßrigem oder organischem Lösungsmittel in Kontakt gebracht, beispielsweise durch Beträufeln, Sprühen oder Eintauchen, gegebenenfalls unter Vakuum,
6. f) dann wird gegebenenfalls das Implantat getrocknet, vorzugsweise bis das Lösungsmittel aus Schritt e) verdampft ist,
7. g) dann wird gegebenenfalls Schritt e) gegebenenfalls gefolgt von Schritt f), vorzugsweise mehrfach, insbesondere 1 bis 5-fach, wiederholt sowie
8. h) gegebenenfalls wird anschließend das Implantat ein- oder mehrfach mit Wasser oder isotoner Saline gespült und
9. i) gegebenenfalls wird anschließend getrocknet.

A further subject of the invention is a method for the production of an implant according to the invention with the following steps:

1. a) at least one consisting of a metal or a metal alloy, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 4, 6 or 7 to 10, with a ceramic coating, in particular Alumina, coated,
   or
2. b) at least one of a polymer, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 5 to 10,
   or
3. c) an implant according to one of claims 1 to 10, which is coated with a polymerized or surface-polymerizing coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel / polyurethane blend,
   or
4. d) an implant according to any one of claims 4, 6 or 7 to 10 with at least one of a metal or a metal alloy existing, homogeneous or formed from different strands, closed or perforated layer or surface into which are introduced by means of a laser wells which are filled with FK506, and then the implant is coated with a polymerized or surface-polymerizing preferably biodegradable coating,
   is used,
5. e) then the implant according to a), b), c) or d) is brought into contact with a FK506 solution in an aqueous or organic solvent, for example by dribbling, spraying or dipping, optionally under vacuum,
6. f) then, if appropriate, the implant is dried, preferably until the solvent from step e) has evaporated,
7. g) then optionally step e) optionally followed by step f), preferably several times, in particular 1 to 5 times, repeated and
8. h) optionally, then the implant is rinsed one or more times with water or isotonic saline and
9. i) if appropriate, then dried.

This process is particularly preferred if in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 0.5-5 g / l FK506 in ethanol and / or that in step e) the implant preferably under vacuum overnight by immersion with a FK506 solution in aqueous or organic solvent is brought into contact and / or that steps f) and / or g) are not performed and / or that in step h) the implant is washed several times with saline and / or that in step i) the implant is dried overnight.

A particularly preferred alternative of the method according to the invention is when, in step e), the implant, preferably sterile, is introduced into a preferably sterile vessel with a perforable closure occluding at the end of a perforation, for example into an injection vial, FK506- Solution, preferably sterile, is filled into the vessel, this is closed with the closing at the end of a perforation, perforable closure, a thin, preferably sterile, air-permeable ventilation tube, such as a cannula, perforated by the closure is inserted, created a vacuum and Preferably, the FK506 solution is kept in motion and finally preferably after about 12 hours the thin, preferably sterile, air-permeable ventilation tube is removed and / or that in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 3.3 mg FK 506 in 1 ml of ethanol and / or that the implant remains until use in the sterile closed glass vessel of step e) and / or that steps f) to i) are omitted.

This alternative method is particularly favorable, hitherto completely unknown and extremely advantageous both in terms of costs and production time and steps, especially since the implant is immediately produced in sterile packaging. It is also generally applicable and of course not limited to FK506 but works with a wide variety of agents. However, such cheap and simple methods are lacking, so that there is a problem here.

1. a) das Implantat wird, vorzugsweise steril, in ein vorzugsweise steriles Gefäß mit einem sich nach Ende einer Perforation verschließenden, perforierbarem Verschluß, beispielsweise in eine Injektions-Flasche eingebracht
2. b) vorzugsweise sterile Wirkstofflösung, vorzugsweise in einem organischen Lösungsmittel mit geringem Dampfdruck, insbesondere in Alkohol wie Ethanol oder Methanol, wird in das Gefäß eingebracht.
3. c) das Gefäß wird mit dem sich nach Ende einer Perforation verschließenden, perforierbarem Verschluß verschlossen,
4. d) ein dünnes, vorzugsweise steril, luftdurchlässiges Belüftungsrohr, beispielsweise eine Kanüle, wird perforierend durch den Verschluß gesteckt wird,
5. e) gegebenenfalls wird ein Vakuum angelegt, wobei vorzugsweise die Wirkstoff-Lösung bewegt wird,
6. f) abschließend, vorzugsweise nach Ablauf von ca. 12h, wird das dünne, vorzugsweise steril, luftdurchlässige Belüftungsrohr entfernt und
7. g) gegebenenfalls das Implantat bis zum Einsatz im vorzugsweise sterilen verschlossenen Glasgefäß von Schritt a) belassen.

A further separate subject of the application is therefore a generally mentioned process for the preparation of active substances coated implants with the following steps:

1. a) the implant is, preferably sterile, in a preferably sterile vessel with a closing at the end of a perforation, perforable closure, for example, introduced into an injection bottle
2. b) preferably sterile drug solution, preferably in an organic solvent with low vapor pressure, especially in alcohol such as ethanol or methanol, is introduced into the vessel.
3. c) the vessel is closed with the perforable closure closing at the end of a perforation,
4. d) a thin, preferably sterile, air-permeable ventilation tube, for example a cannula, is perforated through the closure,
5. e) if appropriate, a vacuum is applied, wherein preferably the active ingredient solution is moved,
6. f) finally, preferably after about 12 hours, the thin, preferably sterile, air-permeable ventilation tube is removed and
7. g) if appropriate, leave the implant until use in the preferably sterile closed glass vessel of step a).

It is favorable for this general method if the implant of step a) has at least one metallic perforated or closed surface or layer, has a ceramic coating, has a polymeric coating and / or has at least one polymeric, open or closed surface or layer.

Also preferred is the general procedure for an implant that is a stent, stent graft, graft, graft connector, polymer surface stent, or catheter.

• (Gruppe 1:) Molsidomin, Linsidomin, Natrium-Nitroprussid, Nitroglycerin oder allgemeinen NO-Donoren; Stimulatoren der löslichen Guanylat-Cyclase (sGC/soluble guanylate cyclase), beispielsweise BAY 41-2272 (5-(Cyclopropyl-2-[1-(2-fluoro-benzyl)-1 H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Hydralazin; Verapamil, Diltiazem, Nifedipin, Nimodipin oder anderen Ca²⁺-Kanal-Blockern; Captopril, Enalapril, Lisinopril, Quinapril oder anderen Inhibitoren Angiotensin umwandelnder Enzyme (angiotensin converting enzyme inhibitors); Losartan, Candesartan, Irbesartan, Valsartan oder anderen Antagonisten des Angiotensin II-Rezeptors ;
• (Gruppe 2:) Dexamethason, Betamethason, Prednison oder Corticosterioden; FK506 (Tacrolimus); 17-beta-Östradiol; Cyclosporin; Mycophenol-Säure; VEGF, VEGF-Rezeptor Aktivatoren; Tranilast; Meloxicam, Celebrex, Vioxx oder anderen COX-2 Antagonisten; Indomethacin, Diclofenac, Ibuprofen, Naproxen oder anderen COX-1-Inhibitoren; Inhibitoren des Plasminogen Aktivators-1 (plasminogen activator inhibitors-1) oder Serpinen; Thrombin Inhibitoren, beispielsweise Hirudin, Hirulog, Agratroban, PPACK; Interleukin-10;
• (Gruppe 3:) Sirolimus, Rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)-Rapamycin oder anderen Rapamycin-Derivativen; PDGF-Antagonisten; Paclitaxel oder 7-Hexanoyl-Taxol; Cisplatin; Vinblastin; Mitoxantron; Combretastatin A4; Topotecan; Methotrexat; Flavopiridol;
• Actinomycin D; Rheopro/Abciximab oder Probucol

insbesondere ausgewählt ist aus

• (Gruppe 1:) Molsidomin, Linsidomin, Natrium-Nitroprussid, Nitroglycerin oder allgemeinen NO-Donoren; Stimulatoren der löslichen Guanylat-Cyclase (sGC/soluble guanylate cyclase), beispielsweise BAY 41-2272 (5-(Cyclopropyl-2-[1-(2-fluoro-benzyl)-1 H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Captopril, Enalapril, Lisinopril, Quinapril oder anderen Inhibitoren Angiotensin umwandelnder Enzyme (angiotensin converting enzyme inhibitors); Losartan, Candesartan, Irbesartan, Valsartan oder anderen Antagonisten des Angiotensin II-Rezeptors;
• (Gruppe 2:) Dexamethason, Betamethason, Prednison oder Corticosterioden; FK 506 (Tacrolimus); VEGF, VEGF-Rezeptor Aktivatoren; Inhibitoren des Plasminogen Aktivators-1 (plasminogen activator inhibitors-1) oder Serpinen;
• (Gruppe 3:) Sirolimus, Rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)-Rapamycin oder anderen Rapamycin-Derivativen; PDGF-Antagonisten; Paclitaxel oder 7-Hexanoyl-Taxal; Mitoxantron, Combretastatin A4; Flavopiridol.

Preferably, the general method is further when the active ingredient is selected from pharmaceutically active substances such as, for example Immunosuppressants or antibiotics, preferably selected from the following active ingredients or their derivatives

• (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine 3-yl] -pyrimidin-4-ylamines), hydralazine, verapamil, diltiazem, nifedipine, nimodipine or other Ca ²⁺ channel blockers, captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors Losartan, candesartan, irbesartan, valsartan or other angiotensin II receptor antagonists;
• (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK506 (tacrolimus); 17-beta-estradiol; cyclosporine; Mycophenolic acid; VEGF, VEGF receptor activators; tranilast; Meloxicam, Celebrex, Vioxx or other COX-2 antagonists; Indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; Thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK; Interleukin-10;
• (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; Topotecan; methotrexate; flavopiridol;
• Actinomycin D; Rheopro / abciximab or probucol

in particular is selected from

• (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine 3-yl] -pyrimidin-4-ylamines); captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors; losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor;
• (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (tacrolimus); VEGF, VEGF receptor activators; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins;
• (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives, PDGF antagonists, paclitaxel or 7-hexanoyl taxal, mitoxantrone, combretastatin A4, flavopiridol.

Another object of the invention is the use of an implant according to the invention for the treatment or prophylaxis of coronary or peripheral vascular constrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis.

Another important subject matter of the application is the use of FK506 mentioned in the following FK506 for coating or for producing an implant for treatment or prophylaxis coronary or peripheral vasoconstriction or occlusions, in particular constrictions or stenoses or restenoses, preferably for the prevention of restenosis.

For FK506 use, it is preferred if the implant is a stent, a stent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, a stent graft, a graft or a graft Connector, in particular a stent or a stent graft or a polymer surface stent.

Further, it is beneficial for the FK506 uses if the FK506 is attached or attached to the implant so that it is released after implantation of the implant, preferably delayed.

Another separate subject of the application is the use of FK506 for the treatment or prophylaxis of coronary or peripheral vasoconstriction or occlusions, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis. As stated above, FK506, as found in this application, has particularly favorable properties.

Within the scope of the invention, a stent or a graft or a stent graft comprising a polymer layer or consisting of polymers has proved particularly suitable for FK506. Such implants, collectively referred to as polymer surface stents in the context of this invention, have not heretofore been used with drug coating. But just this they are proven to be excellent in the context of this application investigations, since they are easy to load with active ingredient and then release the drug evenly and effectively again. These However, property is not limited to FK506, so that another separate subject of the application is a polymer surface stent containing in chemically covalently or non-covalently bound or physically fixed form at least one physiologically and / or pharmaceutically active agent. For the purposes of this invention, the term polymeric surface stent is understood to mean an intravascular implant in the sense of the invention which has a polymer surface. In a broader sense, polymer surface stents thus include grafts and stent grafts, graft connectors, polymer coated or polymeric stents, in the narrower sense, polymer coated or polymeric stents, and stent grafts.

• (Gruppe 1:) Molsidomin, Linsidomin, Natrium-Nitroprussid, Nitroglycerin oder allgemeinen NO-Donoren; Stimulatoren der löslichen Guanylat-Cyclase (sGC/soluble guanylate cyclase), beispielsweise BAY 41-2272 (5-(Cyclopropyl-2-[1-(2-fluoro-benzyl)-1 H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine): Hydralazin; Verapamil, Diltiazem, Nifedipin, Nimodipin oder anderen Ca²⁺-Kanal-Blockern; Captopril, Enalapril, Lisinopril, Quinapril oder anderen Inhibitoren Angiotensin umwandelnder Enzyme (angiotensin converting enzyme inhibitors); Losartan, Candesartan, Irbesartan, Valsartan oder anderen Antagonisten des Angiotensin II-Rezeptors;
• (Gruppe 2:) Dexamethason, Betamethason, Prednison oder Corticosterioden; FK 506 (Tacrolimus); 17-beta-Östradiol; Cyclosporin; Mycophenol-Säure; VEGF, VEGF-Rezeptor Aktivatoren; Tranilast; Meloxicam, Celebrex, Vioxx oder anderen COX-2 Antagonisten; Indomethacin, Diclofenac, Ibuprofen, Naproxen oder anderen COX-1-Inhibitoren; Inhibitoren des Plasminogen Aktivators-1 (plasminogen activator inhibitors-1) oder Serpinen; Thrombin Inhibitoren, beispielsweise Hirudin, Hirulog, Agratroban, PPACK; Interleukin-10;
• (Gruppe 3:) Sirolimus, Rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)-Rapamycin oder anderen Rapamycin-Derivativen; PDGF-Antagonisten; Paclitaxel oder 7-Hexanoyl-Taxol; Cisplatin; Vinblastin; Mitoxantron; Combretastatin A4; Topotecan; Methotrexat; Flavopiridol;
• Actinomycin D; Rheopro/Abciximab oder Probucol

insbesondere ausgewählt ist aus

• (Gruppe 1:) Molsidomin, Linsidomin, Natrium-Nitroprussid, Nitroglycerin oder allgemeinen NO-Donoren; Stimulatoren der löslichen Guanylat-Cyclase (sGC/soluble guanylate cyclase), beispielsweise BAY 41-2272 (5-(Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Captopril, Enalapril, Lisinopril, Quinapril oder anderen Inhibitoren Angiotensin umwandelnder Enzyme (angiotensin converting enzyme inhibitors); Losartan, Candesartan, Irbesartan, Valsartan oder anderen Antagonisten des Angiotensin II-Rezeptors;
• (Gruppe 2:) Dexamethason, Betamethason, Prednison oder Corticosterioden; FK 506 (TaGrolimus); VEGF, VEGF-Rezeptor Aktivatoren; Inhibitoren des Plasminogen Aktivators-1 (plasminogen activator inbibitors-1 oder Serpinen;
• (Gruppe 3:) Sirolimus, Rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)-Rapamycin oder anderen Rapamycin-Derivativen; PDGF-Antagonisten; Paclitaxel oder 7-Hexanoyl-Taxol; Mitoxantron; Combretastatin A4; Flavopiridol;

und/oder daß der Polymeroberflächen-Stent mindestens zwei, vorzugsweise 2 oder 3 physiologisch und/oder pharmazeutisch wirksame Wirkstoffe ausgewählt aus einer der Gruppen 1 bis 3 enthält, vorzugsweise maximal einen Wirkstoff aus einer Gruppe.For the polymer surface stent it is preferred, when the active ingredient is selected from pharmaceutical agents such as immunosuppressants or antibiotics, preferably selected from the following drugs or their derivatives

• (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine 3-yl] -pyrimidin-4-ylamines): hydralazine, verapamil, diltiazem, nifedipine, nimodipine or other Ca ²⁺ channel blockers, captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors Losartan, candesartan, irbesartan, valsartan or other angiotensin II receptor antagonists;
• (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (tacrolimus); 17-beta-estradiol; cyclosporine; Mycophenolic acid; VEGF, VEGF receptor activators; tranilast; Meloxicam, Celebrex, Vioxx or other COX-2 antagonists; Indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; Thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK; Interleukin-10;
• (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; Topotecan; methotrexate; flavopiridol;
• Actinomycin D; Rheopro / abciximab or probucol

in particular is selected from

• (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine) 3-yl] -pyrimidin-4-ylamines); captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors; losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor;
• (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (TaGrolimus); VEGF, VEGF receptor activators; Inhibitors of plasminogen activator-1 (plasminogen activator inbibitors-1 or serpins;
• (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; mitoxantrone; combretastatin A4; flavopiridol;

and / or that the polymer surface stent contains at least two, preferably 2 or 3 physiologically and / or pharmaceutically active substances selected from one of the groups 1 to 3, preferably at most one active substance from a group.

For a further preferred embodiment of this polymer surface stent, if the other active ingredient is selected from Group 1 above, it is released from the implant within the first 24-72 hours after implantation and / or, if the other active ingredient is selected from the preceding Group 2 released from the implant within the first 48 h-21 days after implantation and / or, if the additional active substance is selected from Group 3 above, released from the implant within 14 days to 3 months after implantation.

Generally, for polymer surface stents of the present invention, all of the above-described embodiments and types, methods of manufacture, and uses of the particular FK506-containing implant are also preferred for the inventive polymer surface stent and are therefore articles of this invention as long as the embodiments are still polymer surface stents.

A further subject of the invention is also the treatment of a human or animal which requires this treatment with or through an implant according to the invention or a polymer surface stent.

In the following section, the invention is further illustrated by examples without being limited thereto.

Examples and illustrations: pictures:

Figure 1 shows the release of FK506 from a coronary stent graft in which the PTFE surface was loaded with FK506.

Figure 2 shows the release of candesartan and quinapril from a stent graft in which the PTFE surface was coated with candesartan and quinapril.

Figure 3 shows the release of candesartan and quinapril from a polyurethane coated stent enriched with candesartan and quinapril.

Figure 4 shows the release of candesartan and quinapril from a polyurethane / hydrogel blend coated stent that was enriched with candesartan and quinapril.

Figure 5 shows the release of FK506 in the blood after implantation of appropriately coated stents in rabbits.

Figure 6 shows the area of the intima on implanted stents with and without appropriate coating with FK506.

Figure 7 shows the inflammatory response to implantation of stents with and without appropriate coating with FK506.

Examples: Example 1: Loading interesting links on stent grafts

• A: Versuche mit gelösten Feststoffen, bei denen Stent Grafts mit einer PTFE-Polymerschicht in die Lösung eingetaucht wurden.
• B: Versuche mit i.v.-Lösungen, bei denen Stent Grafts mit einer PTFE-Polymerschicht in die Lösung eingetaucht wurden.
• C: Versuche mit i.v.-Lösungen, bei denen mit Polyurethan beschichtete Stents in die Lösung eingetaucht wurden.

All values are given in μg. <b> Table 1 </ b> Active substance / stent type FK 506 (tacrolimus) vinblastine Paclitaxel (taxol) cisplatin mitoxantrone A 1382 74 128 15 * 116 1671 125 155 14 * 142 1625 238 148 14 * 113 average 1559 146 144 14 124 B 18 16 21 average 18 C 194 165 average 180 * measured by AAS

• A: Solids testing in which stent grafts with a PTFE polymer layer were immersed in the solution.
• B: Experiments with iv solutions in which stent grafts with a PTFE polymer layer were immersed in the solution.
• C: Experiments with iv solutions in which polyurethane-coated stents were immersed in the solution.

Example 2: Release patterns of differently prepared inventive stent grafts as well as general polymer surface stents:

All values are given in μg.

For drug release analysis, a stent was incubated at 37 ° C in 10 ml of PBS buffer (stabilized with Na azide) at 37 ° C. After expiry of defined periods of time, 2 × 1 ml of the solution were removed and analyzed. These 2 ml were replaced with fresh PBS buffer (stabilized with Na azide).

The tables show the total released content of active ingredient in the solution. That is, the amount of active ingredient in the buffer volume removed for analysis was added to the amount withdrawn at the subsequent time. <b> Table 2: </ b> Vinblastine active ingredient / Art after 1 h after 3 h after 8 h after 24 h after 96 h
after 72 h A 73 and 75 section: 74 108 and 114 section: 109 121 and 126 section: 124 106 and 120 section: 113 132 and 140 (96h) Section: 136 37 and 41 section: 39 48 and 51 cut: 50 47 and 58 section: 42 57 and 62 Cut: 60 56 and 57 (72h) Intersection: 57 80 and 86 Cut: 83 99 and 104 section: 102 108 and 117 section: 113 117 and 127 section: 122 113 and 121 (72h) Intersection: 117 A: Solids testing in which stent grafts with a PTFE polymer layer were immersed in the solution. FK 506 (tacrolimus) after 1h after 3 h after 8 h after 24 h after 96 h after 192 h Active substance / type A 1. Stent 14 and 13 cut: 14 62 and 62 Section: 62 92 and 99 section: 95 148 and 145 section: 147 145 and 151 section: 148 195 and 198 Cut: 196 after 1 h after 3 h after 8 h after 24 h after 96 h A 2nd stent 34 and 26 section: 30 56 and 57 Section: 57 82 and 78 Section: 80 108 and 109 section: 109 159 and 164 Editing: 161 after 1 h after 3 h after 8 h after 24 h after 96 h A 3rd stent 12 and 9 cut: 11 47 and 43 cut: 45 101 and 93 section: 95 154 and 155 section: 154 184 and 190 editing: 187 A: Solids testing in which stent grafts with a PTFE polymer layer were immersed in the solution. FK 506 (tacrolimus) after 1 h after 3 h after 8 h after 24 h after 96 h Active substance / kind
C
1st stent 19 and 20 cut: 20 25 and 26 cut: 26 33 and 33 section: 33 41 and 39 section: 40 43 and 38 section: 41 C
2nd stent after 1 h after 3 h after 8 h after 24 h after 96 h after 264 h 20 and 27 section: 24 21 and 24 cut: 22 26 and 30 cut: 28 34 and 31 cut: 32 37 and 35 cut: 36 85 after 367 h 88 and 94 section: 91 C: Experiments with iv solutions in which polyurethane-coated stents were immersed in the solution. paclitaxel after 1 h after 3 h after 8 h after 24 h after 96 h after 192 h Drug / Art A 0.14 and 0.23 average: 0.19 0.46 and 0.53 average: 0.50 1.42 and 1.25 cut: 1.34 1.65 and 1.42 Cut: 1.54 1.42 and 1.93 Cut: 1.68 2.22 and 2.24 Cut: 2.23 0.42 and 0.52 average: 0.47 0.90 and 0.90 average: 0.90 1.16 and 1.21 cut: 1.19 2.44 and 2.40 Cut: 2.42 2.79 and 2.18 cut: 2.79 0.20 and 0.16 cut: 0.18 0.51 and 0.95 average: 0.73 0.89 and 0.94 average: 0.92 2.26 and 2.27 Cut: 2 .27 2.82 and 2.82 Editing: 2.82 A: Solids testing in which stent grafts with a PTFE polymer layer were immersed in the solution. cisplatin after 1 h after 3 h after 8 h After 24 h Active substance / kind A 11.7 and 91.9 Cut: 11.8 15.4 and 15.4 Cut: 15.4 16.3 and 16.5 editing: 16.4 16.1 and 15.9 Cut: 16.0 5.7 and 5.4 Section: 5.5 7.8 and 7.7 Section: 7.8 9.9 and 9.8 Cut: 9.8 10.9 and 11.1 Cut: 11.0 10.0 and 10.0 average: 10.0 11.4 and 11.8 Cut: 11.6 12.2 and 12.3 Section: 12.2 12.4 and 12.2 section: 12.3 A: Solids testing in which stent grafts with a PTFE polymer layer were immersed in the solution. mitoxantrone after 1 h after 3 h after 8 h after 24 h Active substance / kind A 57 and 86 section: 71 55 and 52 cut: 54 49 and 47 cut: 48 42 and 49 cut: 45 70 and 74 Cut: 72 80 and 83 Cut: 81 80 and 82 cut: 81 72 and 75 cut: 74 29 and 27 section: 28 25 and 27 section: 26 23 and 21 cut: 22 24 and 29 cut: 27 A: Solids testing in which stent grafts with a PTFE polymer layer were immersed in the solution.

Example 3: Manufacturing process (1) for FK506 coated implants:

• 10 mg of FK506 are dissolved in 3 ml of ethanol
• Stainless steel uncoated stents are immersed in the solution under vacuum overnight at room temperature.
• Wash with saline three times for 1 minute
• Dry overnight.

Example 4: Manufacturing Method (2) for FK506 Coated Stent Grafts:

• The dosage of FK506 may vary according to stent length and diameter, as well as after application in the body. Here, a dosage of 10-200 μg FK506 per cm stent length was used.
• FK506 is dissolved in ethanol in a small glass vessel (according to the desired dosage) and the solution visually checked for crystals.
• The non-pretreated stent grafts ("JOSTENT Coronary Stent Graft"), consisting of a sandwich construction of two stents made of stainless steel with a PTFE membrane, are mounted on brackets.
• Using a pipette, pipet the appropriate amount of FK506 solution (5 to 30 μl) onto the assembled Stent Graft.
• This step can be repeated as desired to apply larger quantities of FK506 to the implant, usually one or two times. In the present case, the process was repeated once.
• After the Stent Graft is fully loaded, it is carefully pushed off the bracket.
• After a short drying in air (about 5 min), optionally with heat, the stents can be packaged.
• All stents are examined under the magnifying glass for drug flocculation and discarded if necessary.

Example 5: Manufacturing method (3) for FK506 coated stent having a ceramic coating:

• 50 mg FK506 are dissolved in 10 ml ethanol in a glass jar. If necessary, all further concentrations of this stock solution are prepared by dilution (dilutions between 1: 1 and 1:20).
• The solution is visually checked for crystals.
• The unloaded, with an alumina layer (according to PCT application WO 00/25841 , see also example 7 for ceramic coating) coated stents are mounted on brackets.
• With a syringe, the FK506 solution (5 to 50 μl) is applied dropwise to the stent. The solution should be distributed over the complete stent.
• The loaded stent is carefully removed from the holder.
• After a short drying in air (about 5 min), optionally with heat, the stents can be packaged.
• All stents are examined under the magnifying glass for drug flocculation and discarded if necessary.

Example 6: New alternative production method (4) (applicable inter alia to FK506 but also to other active substances), in particular for the production of sterile stents, stent grafts or polymer surface stents:

• Small injection bottles are used which are not much larger than the stent.
• Sterile coronary stent grafts (CSG's) are placed sterile in the sterile injection vials.
• Add 0.5 ml sterile-filtered FK506 solution (3.3 mg / ml in ethanol) to the bottle.
• The surfaces are closed with rubber plugs.
• A sterile sterile cannula syringe is pricked through the center of the rubber stopper.
• The bottles are placed horizontally on a roller in a desiccator under vacuum.
• The bottles are rolled under vacuum overnight.
• The injection needle is removed.
• It is not flushed.
• The sterile CSGs are ready for use.

Example 7: A selection of possible active ingredients for an active substance-releasing stent, in particular with several layers, for example polymer-surface stents or stent grafts, etc.

The loading methods are described as technical approaches below.

The listed active ingredients also include derivatives as well as all types of salts, enantiomers, racemates, bases or free acids.

Of particular interest here are stents, stent grafts and polymer surface stents which contain at least one, two or three of the active ingredients listed below and release them accordingly.

The enumerated active substances are classified according to their preferred release profile or the release period into groups 1 - 3.

It is also preferred if the stents, stent grafts or polymer surface stents contain active substances from different groups. <b> Table 8 </ b> Phase I - Vasodilation (Group 1) Active ingredients that are released in particular within the first 24-72 h after placement of the stent. active substance Molsidomine, linsidomine, sodium nitroprusside, nitroglycerin, NO donors in general Soluble guanylate cyclase stimulators such as BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridin-3-yl] -pyrimidine-4 -ylamine) hydralazine Verapamil, diltiazem, nifedipine, nimodipine and other Ca ²⁺ channel blockers Captopril, enalapril, lisinopril, quinapril and other inhibitors of angiotensin converting enzymes Losartan, candesartan, irbesartan, valsartan and other angiotensin II receptor antagonists Phase II - Inhibition of inflammation, immunosuppression, promotion of cell growth of endothelial cells, inhibition of cell migration (Group 2) Active ingredients that are released in particular within the first 2-21 days after placement of the stent. active substance Dexamethasone, betamethasone, prednisone and other corticosteroids 17-beta-estradiol FK506 (tacrolimus) cyclosporine mycophenolic acid VEGF, VEGF receptor activators tranilast Meloxicam, Celebrex, Vioxx and other COX-2 antagonists Indomethacin, diclofenac, ibuprofen, naproxen and other COX-1 inhibitors Plasminogen activator inhibitor-1 and other serpins Thrombin inhibitors such as hirudin, hirulog, agratroban, PPACK etc. Interleukin-10 Phase III - Inhibition of Cell Proliferation (Group 3) Active ingredients that are released in particular within the first 14 days to 3 months after placement of the stent. active substance Sirolimus, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin and other rapamycin derivatives PDGF antagonists paclitaxel cisplatin vinblastine mitoxantrone Combretastatin A4 topotecan methotrexate flavopiridol

• Keramische Beschichtung
  Eine Aluminiumoxid-Beschichtung (Patentanmeldungen DE 19855421 , DE 19910188 , WO 00/25841 ) mit poröser Oberfläche kann mit Wirkstoff (beispielsweise FK506 mit Mengen zwischen 10 µg und 10 mg) entweder durch Eintauchen, Aufsprühen oder eine vergleichbare Technik beladen werden. Die Dosis des Wirkstoffes hängt von der Art des Zielgefäßes und dem Zustand des Patienten ab und wird so gewählt, daß Proliferation, Migration und T-Zell-Antwort ausreichend inhibiert werden, ohne daß der Heilungsprozeß behindert wird. Der Wirkstoff kann als wässrige oder organische Lösung, beispielsweise in DMSO, DMF und Ethanol, verwendet werden. Nach dem Sprühen oder Eintauchen (unter schwachem Vakuum) wird der behandelte Stent getrocknet und der Vorgang 1 bis 5-mal wiederholt. Nach dem letzten Trockenschritt wird der Stent 1 min lang bei Raumtemperatur in Wasser oder isotonischer Saline gespült und anschließend wieder getrocknet. Der Wirkstoffgehalt kann nach Herauslösen des Wirkstoffs mit einem geeigneten Lösungsmittel durch Standardmethoden (HPLC, LC-MS) analysiert werden. Freisetzungskinetiken können unter Verwendung einer Standard-Freisetzungsmeßapparatur gemessen werden.
• PTFE Membran: Stent Graft
  Hier wird ein zu oben beschrieben identischer Ansatz verwendet. Der Wirkstoff wird in den Vertiefungen der porösen PTFE-Membran eingelagert.
• Allgemeine polymerische Beschichtung
  Verschiedene Polymere sind für eine Wirkstoffbeladung geeignet: Methacrylate-Polymere, Polyurethan-Beschichtungen, PTFE-Beschichtungen oder Hydrogel-Beschichtungen. Der Wirkstoff kann entweder auf die End-Oberfläche aufgetragen werden (s.o.) oder wird direkt der Polymerisationslösung beigegeben. In den übrigen Details entspricht dieser technische Ansatz den oben bereits beschriebenen.
• Mechanischer Ansatz
  Der mechanische Ansatz beruht auf Vertiefungen, die in die Stent-Streben mittels eines Schneid-Lasers eingebracht werden. Diese Vertiefungen können dann mit Wirkstoff gefüllt werden. Der mechanische (Vertiefungen)-Ansatz kann mit einer dünnen bioabbaubaren Beschichtung kombiniert werden, die selbst wirkstoffbeladen ist. Nach einer anfänglichen Freisetzung aus der bioabaubaren Beschichtung kann aus den wirkstoffgefüllten Vertiefungen langfristig Wirkstoff freigesetzt werden. In den übrigen Details entspricht dieser technische Ansatz den oben bereits beschriebenen.

Local application of the drug is achieved by direct delivery from the drug-loaded surface of a coronary or peripheral stent. A drug-loaded surface of a stent can be achieved by using various technological approaches. Each of these approaches can be carried out so that the active ingredient is released from the surface either in a short (hours) or an extended period (days). The release kinetics can be adjusted by making specific modifications to the surface, eg hydrophobic or hydrophilic side chains of a polymeric carrier or a ceramic surface.

• Ceramic coating
  An alumina coating (patent applications DE 19855421 . DE 19910188 . WO 00/25841 ) with a porous surface can be loaded with active ingredient (for example FK506 in amounts between 10 μg and 10 mg) either by immersion, spraying or a comparable technique. The dose of the drug depends on the nature of the target vessel and the condition of the patient and is chosen so as to sufficiently inhibit proliferation, migration and T cell response without hindering the healing process. The active ingredient can be used as an aqueous or organic solution, for example in DMSO, DMF and ethanol. After spraying or dipping (under low vacuum), the treated stent is dried and the procedure repeated 1 to 5 times. After the last drying step, the stent is rinsed for 1 min at room temperature in water or isotonic saline and then dried again. The active ingredient content can be analyzed by dissolving the active ingredient with a suitable solvent by standard methods (HPLC, LC-MS). Release kinetics can be measured using a standard release measuring apparatus.
• PTFE membrane: stent graft
  Here, an identical approach to that described above is used. The active ingredient is incorporated in the wells of the porous PTFE membrane.
• General polymeric coating
  Various polymers are suitable for drug loading: methacrylate polymers, polyurethane coatings, PTFE coatings, or hydrogel coatings. The active ingredient can either applied to the final surface (see above) or added directly to the polymerization solution. In the remaining details this technical approach corresponds to that already described above.
• Mechanical approach
  The mechanical approach relies on indentations that are introduced into the stent struts by means of a cutting laser. These wells can then be filled with active ingredient. The mechanical (wells) approach can be combined with a thin biodegradable coating that itself is drug loaded. After an initial release from the biodegradable coating, active ingredient can be released in the long term from the drug-filled wells. In the remaining details this technical approach corresponds to that already described above.

Example 8: Release of candesartan and quinapril from (polymer-) coated implants:

• a) Stents were equipped with a porous PTFE membrane. This membrane was then loaded with a drug mixture of candesartan and quinapril (1 mg each). The two active ingredients are released simultaneously. The release was determined in PBS (phosphate buffered saline). Figure 2 shows the drug release of candesartan and quinapril from the stent.
• b) Open-cell stainless steel stents were provided with a polyurethane coating. An active substance mixture of candesartan and quinapril (15% in each case based on the polyurethane content) was introduced into a 5% strength solution of the polyurethane in dimethylacetamide and applied to the stent by means of a spray method. Figure 3 shows the corresponding drug release.
• d) Open-cell stainless steel stents were provided with a polyurethane / hydrogel coating. An active substance mixture of candesartan and quinapril (15% in each case based on the polymer content) was introduced into a 5% solution of the polymer blend in dimethylacetamide and applied to the stent by means of a spray method. Figure 4 shows the corresponding drug release.

Example 9: Study on the release kinetics and mode of action of FK506 in animals

Coronary stainless steel stents (JOSTENT Flex, 16 mm) were coated with a ceramic layer of alumina. This coating served as a carrier of FK506 (as described in Example 5 and Example 7 under "Ceramic Coating"). In this case, the stents were loaded with a total of 60 μg FK506. In an animal study, these FK506 coated stents and normal non-coated stents were implanted in rabbits (n = 7) in the carotid artery of New Zealand rabbits. The release of FK506 was investigated as well as the effect of FK506 on the growth of the intima and the formation of macrophages and lymphocytes.

The release of FK506 was determined by HPLC determination of the amount of FK506 in the blood of the rabbits after 1 h, 8 h, 24 h and 48 h. Figure 5 clearly shows a very good release kinetics of FK506 over time. The rabbits were killed after 28 days and the implanted stents examined. The area of the newly grown intima (neointima) within the stent was quantified under the light microscope. Figure 6 clearly shows that the formation of neointima in the ceramic-coated stents loaded with FK506 is significantly reduced compared to normal stents. When loaded with 60 μg FK506, there is a reduction of 53%. In addition, this reduction was accompanied by a noticeable reduction in the sources of inflammation. As can be seen in Figure 7, macrophages and lymphocyte formation are significantly reduced compared to the normal stent.

The use of stents with a ceramic coating, to which FK506 is applied, thus leads after implantation to a significant reduction of neointima as well as of inflammatory foci.

Claims (43)

Implant containing in chemically covalently or non-covalently bound or physically fixed form FK506 and optionally at least one further active ingredient. Implant according to claim 1, characterized in that it is an intracavernous, preferably intravascular, implant. Implant according to one of claims 1 or 2, characterized in that the implant is suitable for the treatment or prophylaxis of coronary or peripheral vasoconstrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis. Implant according to one of claims 1 to 3, characterized in that the implant has at least one of a metal or a metal alloy, homogeneous or formed of different strands, closed or openwork layer or surface. Implant according to one of Claims 1 to 4, characterized in that the implant has at least one closed or perforated layer or surface made of a polymer, homogeneous or formed from different strands. Implant according to claim 5, characterized in that at least one polymer layer is wholly or partially made of a metal or a metal alloy, homogeneous or formed from different strands, closed or perforated layer or surface, preferably one consisting of a metal or a metal alloy, optionally lattice-shaped structure covered. An implant according to claim 5, characterized in that the implant comprises at least one closed or perforated layer or surface consisting of a metal or a metal alloy, homogeneous or of different strands and at least one closed, homogeneous or formed of a different strand or perforated layer or surface. An implant according to claim 7, characterized in that the layer or surface consisting of a metal or a metal alloy is a possibly lattice-like structure consisting of a metal or a metal alloy and / or the layer or surface consisting of a polymer is homogeneously closed or woven and / or is water and / or Korpuskelundurchlässig and / or the sequence of the layers and surfaces from outside to inside metal polymer, polymer metal, metal polymer metal or polymer metal polymer and / or either one of Polymeric layer or surface is not chemically (covalently or noncovalently bonded) to the metal or metal alloy layer or surface or polymer layer or surface by means of an adhesive with the metal or metal alloy layer or surface connected is. Implant according to one of claims 5 to 8, characterized in that the polymer is selected from Dacron; Polytetrafluoroethylene (PTFE / Teflon), expandable or non-expandable; polyurethane; Methacrylate polymers; Hydrogel or hydrogel / polyurethane blend, preferably of polytetrafluoroethylene (PTFE), expandable or non-expandable; or polyurethane; in particular made of PTFE. Implant according to one of claims 1 to 9, characterized in that the implant is a stent, a stent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, a stent graft, or a graft a graft connector, in particular a stent or a stent graft. Implant according to one of claims 1 to 10, characterized in that the implant is coated with FK506. Implant according to one of claims 4, 6 or 7 to 10, characterized in that the implant has a ceramic coating, in particular of aluminum oxide or iridium oxide, to which FK506 is bound. Implant according to claim 12, characterized in that the ceramic coating is completely or partially covered with a polymeric, preferably biodegradable, coating to which optionally FK506 and / or another active substance is bound or in which FK506 and / or another active ingredient Application of the coating has been solved. Implant according to one of claims 5 to 10 or 13, characterized in that the implant comprises a polymeric coating, in particular from methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel / polyurethane blend, in particular PTFE, is bound to the FK506 or was dissolved in the FK506 before application of the coating. Implant according to one of claims 4, 6 or 7 to 10, characterized in that the metal of the implant has laser-introduced wells filled with FK506. An implant according to claim 15, characterized in that the FK506-filled wells or at least the wells are coated with a biodegradable polymeric material optionally with FK506 attached to the polymeric coating or with FK506 dissolved in the polymeric material prior to application of the coating has been. Implant according to one of claims 11 to 16, characterized in that FK506 is in the form of loaded nanoparticles or liposomes. Implant according to one of claims 1 to 10 producible by a method in which a) at least one consisting of a metal or a metal alloy, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 4, 6 or 7 to 10, with a ceramic coating, in particular Alumina or lridiumoxid, is used
or b) a closed or formed of a polymer, homogeneous or of different strands broken or surface implant according to any one of claims 5 to 10 is used,
or c) an implant according to one of claims 1 to 10, which is coated with a polymerized or surface-polymerizing coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel / polyurethane blend, is used, or d) an implant according to any one of claims 4, 6 or 7 to 10 with at least one consisting of a metal or a metal alloy, homogeneous or formed from different strands, closed or perforated layer or surface into which recesses are introduced by means of a laser which are filled with FK506 and then the implant is coated with a polymerized or surface-polymerizing biodegradable coating, e) then the implant according to a), b), c) or d) is brought into contact with a FK506 solution in an aqueous or organic solvent, for example by dribbling, spraying or dipping optionally under vacuum, f) then optionally the implant is dried, preferably until the removal of the solvent from step e), g) then, if appropriate, step e) is repeated, if appropriate followed by step f), preferably several times, in particular from 1 to 5 times, and also h) optionally then the implant is rinsed one or more times with water or isotonic saline, and i) optionally subsequently dried. Implant according to claim 18, characterized in that in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 0.5-5 g / l FK506 in ethanol and / or that in step e) the implant is brought into contact, preferably under vacuum, overnight by immersion with an FK506 solution in an aqueous or organic solvent and / or the steps f) and / or g) are not carried out and / or in step h) the implant is washed several times with saline and / or in step i) the implant is dried overnight. An implant according to claim 18, characterized in that in step e) the implant, preferably sterile, is introduced into a preferably sterile vessel with a perforable closure occluding the end of a perforation, for example into an injection bottle, FK506 solution, preferably sterile, is filled into the vessel, this is closed with the closing at the end of a perforation, perforable closure, a thin, preferably sterile, air-permeable ventilation tube, such as a cannula, perforated by the closure is inserted, created a vacuum and preferably the FK506 solution is moved and finally, preferably after about 12 hours, the thin, preferably sterile, air-permeable ventilation tube is removed and / or that in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 3.3 mg FK506 in 1 ml ethanol and / or Im plant remains until use in the preferably sterile closed glass vessel of step e) and / or that steps f) to i) are omitted. An implant according to any one of claims 5 to 10 preparable by a method in which prior to formation of at least one of a polymer consisting, closed or perforated Layer or surface or a polymeric coating of the implant FK506 was dissolved in the polymerization material. Implant according to one of claims 1 to 21, characterized in that after implantation of the implant FK506 is released. Implant according to claim 22, characterized in that the release is delayed. Implant according to claim 23, characterized in that FK506 is released from the implant over a period of 24 h, preferably 48 h, in particular more than 96 h after implantation. Implant according to claim 23, characterized in that the FK506 from the implant after implantation e) within <48 h or f) is liberated for at least 48 h, preferably for at least 7 days, in particular for at least 2 to 21 days,
or that g) the implant shows both release patterns d) and e). Implant according to one of claims 1 to 25, characterized in that the implant contains at least one further active substance, preferably a pharmaceutical active substance, in particular a further active substance selected from the following active substances or their derivatives (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase stimulators (sGC / soluble guanylate cyclase), for example, BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridin-3-yl] -pyrimidin-4-ylamine); hydralazine Verapamil, diltiazem, nifedipine, nimodipine or other Ca ²⁺ channel blockers, captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors; losartan, candesartan, irbesartan, valsartan or other angiotensin antagonists II receptor; (Group 2 :) Dexamethasone, betamethasone, prednisone or other corticosteriodes; 17-beta-estradiol; cyclosporine; Mycophenolic acid; VEGF, VEGF receptor activators; Tranifast; Meloxicam, Celebrex, Vioxx or other COX-2 antagonists; Indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; Thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK; Interleukin-10; (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; Topotecan; methotrexate; flavopiridol, Actinomycin D; Rheopro / abciximab or probucol. An implant according to claim 26, characterized in that , when the further active ingredient is selected from group 1, it is released from the implant within the first 24-72 hours after implantation and / or, when the further active ingredient is selected from group 2, that of Implant is released within the first 48 h - 21 days after implantation and / or if the further active ingredient is selected from group 3, this is released from the implant within 14 days to 3 months after implantation. Process for producing an implant according to one of Claims 1 to 25, comprising the following steps: a) at least one consisting of a metal or a metal alloy, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 4, 6 or 7 to 10, with a ceramic coating, in particular Alumina or iridium oxide, is coated,
or b) at least one of a polymer, homogeneous or formed of different strands, closed or perforated layer or surface having implant according to one of claims 5 to 10,
or c) an implant according to one of claims 1 to 10, which is coated with a polymerized or surface-polymerizing coating, in particular of methacrylate polymers, polyurethane, PTFE, hydrogel or hydrogel / polyurethane blend,
or d) an implant according to any one of claims 4, 6 or 7 to 10 with at least one consisting of a metal or a metal alloy, homogeneous or formed from different strands, closed or perforated layer or surface into which recesses are introduced by means of a laser which are filled with FK506 and then the implant is coated with a polymerized or surface-polymerizing preferably biodegradable coating,
is used, e) then the implant according to a), b), c) or d) is brought into contact with a FK506 solution in an aqueous or organic solvent, for example by dribbling, spraying or dipping, optionally under vacuum, f) then, if appropriate, the implant is dried, preferably until the solvent from step e) has evaporated, g) then optionally step e) optionally followed by step f), preferably several times, in particular 1 to 5 times, repeated and h) optionally, then the implant is rinsed one or more times with water or isotonic saline and i) if appropriate, then dried. A method according to claim 28, characterized in that in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 0.5 to 5 g / l FK506 in ethanol and / or that in step e) the implant under Vacuum preferably by overnight immersion with a FK506 solution in aqueous or organic solvent is brought into contact and / or that the steps f) and / or g) are not performed and / or that at step h) the implant washed several times with saline and / or that in step i) the implant is dried overnight. A method according to claim 28, characterized in that in step e) the implant, preferably sterile, is introduced into a preferably sterile vessel with a perforable closure occluding at the end of a perforation, for example into an injection bottle, FK506 solution, preferably sterile, is filled into the vessel, this is closed with the closing at the end of a perforation, perforable closure is a thin, preferably sterile, air-permeable ventilation tube, such as a cannula, perforating inserted through the closure, created a vacuum and preferably the FK506- Solution is kept in motion and finally preferably after about 12 hours the thin, preferably sterile, air-permeable ventilation tube is removed and / or that in step e) FK506 is dissolved in alcohol, preferably in ethanol, in particular in a concentration of 3.3 mg FK506 in 1 ml of ethanol and / or that the implant remains until use in the sterile closed glass vessel of step e) and / or that steps f) to i) are omitted. Process for the production of implants according to one of Claims 5 to 10, in which prior to the formation of at least one polymeric, closed or perforated layer or surface or a polymeric coating of the implant FK506 has been dissolved in the polymerisation material. Process for the preparation of active substances coated implants comprising the following steps: a) the implant is, preferably sterile, placed in a preferably sterile vessel with a closable after the end of a perforation, perforable closure, for example, in an injection bottle b) preferably sterile drug solution, preferably in an organic solvent with low vapor pressure, especially in alcohol such as ethanol or methanol, is introduced into the vessel. c) the vessel is closed with the perforable closure closing at the end of a perforation, d) a thin, preferably sterile, air-permeable ventilation tube, for example a cannula, is perforated through the closure, e) if appropriate, a vacuum is applied, wherein preferably the active ingredient solution is moved, f) finally, preferably after about 12 hours, the thin, preferably sterile, air-permeable ventilation tube is removed and g) if appropriate, leave the implant until use in the preferably sterile closed glass vessel of step a). A method according to claim 32, characterized in that the implant of step a) has at least one metallic open or closed surface or layer, has a ceramic coating, has a polymeric coating and / or has at least one polymeric, open or closed surface or layer. A method according to any one of claims 32 or 33, characterized in that the implant is a stent, stent graft, graft, graft connector, polymer surface stent or catheter. A method according to any one of claims 32 to 34, characterized in that the active ingredient is selected from pharmaceutical active substances such as immunosuppressants or antibiotics, preferably selected from the following active substances or their derivatives (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Stimulators of soluble guanylate cyclase (sGC / soluble guanylate cyclase), for example BAY 41-2272 (5- (Cydopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine-3 hydralazine; verapamil, diltiazem, nifedipine, nimodipine or other Ca ²⁺ channel blockers; captopril, enalapril, lisinopril, quinapril or other angiotensin converting enzyme inhibitor inhibitors; Losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor; (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (tacrolimus); 17-beta-estradiol; cyclosporine; Mycophenolic acid; VEGF, VEGF receptor activators; tranilast; Meloxicam, Celebrex, Vioxx or other COX-2 antagonists; Indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; Thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK; Interleukin-10; (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; Topotecan; methotrexate; flavapiridol; Actinomycin D; Rheopro / abciximab or probucol in particular is selected from (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Stimulators of soluble guanylate cyclase (sGC), for example BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine-3 captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors; losartan, candesartan, irbesartan, valsartan or other angiotensin II receptor antagonists; (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (tacrolimus); VEGF, VEGF receptor activators; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; mitoxantrone; combretastatin A4; flavopiridol. Use of an implant according to one of claims 1 to 27 for the treatment or prophylaxis of coronary or peripheral vasoconstrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis. Use of FK506 for coating or for producing an implant for the treatment or prophylaxis of coronary or peripheral vasoconstrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis. Use according to claim 37, characterized in that the implant is a stent, a stent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, a stent graft, a graft or a graft connector, in particular a stent or a stent graft or a polymer surface stent. Use according to one of claims 37 or 38, characterized in that the FK506 is bound or attached to the implant in such a way that it is released after implantation of the implant, preferably delayed. Use of FK506 for the treatment or prophylaxis of coronary or peripheral vascular constrictions or closures, in particular constrictions or stenoses or restenoses, preferably for the prophylaxis of restenosis. Polymer surface stent containing in chemically covalently or non-covalently bound or physically fixed form at least one physiologically and / or pharmaceutically active agent. Polymer surface stent according to claim 41, characterized in that the active substance is selected from pharmaceutical agents such as immunosuppressants or antibiotics, preferably selected from the following active substances or their derivatives (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine) 3-yl] -pyrimidin-4-ylamines); hydralazine; verapamil, diltiazem, nifedipine, nimodipine or other Ca ²⁺ channel blockers; Captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme inhibitors (angiotensin converting enzyme inhibitors); Losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor; (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (tacrolimus); 17-beta-estradiol; Cyclosporin, mycophenol acid; VEGF, VEGF receptor activators; tranilast; Meloxicam, Celebrex, Vioxx or other COX-2 antagonists; Indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; Thrombin inhibitors, for example hirudin, hirulog, agratroban, PPACK; Interleukin-10; (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; cisplatin; vinblastine; mitoxantrone; combretastatin A4; Topotecan; methotrexate; flavopiridol; Actinomycin D; Rheopro / abciximab or probucol in particular is selected from (Group 1 :) molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donors; Soluble guanylate cyclase (sGC) stimulants, for example BAY 41-2272 (5- (cyclopropyl-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-n] pyridine) 3-yl] -pyrimidin-4-ylamine); captopril, enalapril, lisinopril, quinapril or others Inhibitors of angiotensin converting enzyme inhibitors (angiotensin converting enzyme inhibitors); Losartan, candesartan, irbesartan, valsartan or other antagonists of the angiotensin II receptor; (Group 2) Dexamethasone, betamethasone, prednisone or corticosteriodes; FK 506 (tacrolimus); VEGF, VEGF receptor activators; Inhibitors of plasminogen activator-1 (plasminogen activator inhibitors-1) or serpins; (Group 3) sirolimus, rapamycin, SDZ RAD (40-O- (2-hydroxyethyl) rapamycin or other rapamycin derivatives; PDGF antagonists; paclitaxel or 7-hexanoyl taxol; mitoxantrone; combretastatin A4; flavopiridol; and / or that the polymer surface stent contains at least two, preferably 2 or 3 physiologically and / or pharmaceutically active substances selected from one of the groups 1 to 3, preferably at most one active substance from a group. The polymer surface stent according to claim 42, characterized in that when the further active ingredient is selected from group 1, it is released from the implant within the first 24-72 hours after implantation and / or, when the further active ingredient is selected from group 2, this is released from the implant within the first 48 h-21 days after implantation and / or, if the additional active substance is selected from group 3, released from the implant within 14 days to 3 months after implantation.

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